Tear film is essential for overall eye health and visual acuity. Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. A true aqueous- deficient dry eye, known clinically as keratoconjunctivitis sicca (KCS) is among the most common (~4 million) complications and is due to inefficient lacrimal gland (LG) function. Despite significant progress in understanding glandular failure during KCS progression, there is currently no therapy for repairing/regenerating the LG to restore tear production. An indicator of LG dysfunction in patients with DED is the loss of parasympathetic innervation, which is essential for LG function and the downregulation of the parasympathetic- derived neurotransmitter neuropeptide Y (NPY). However, the function of innervation and NPY in LG development, homeostasis and regeneration is not known. I hypothesize that parasympathetic nerve-derived NPY regulates LG epithelial morphogenesis and regeneration. In this proposal, I propose to define the role of NPY and its receptors during LG development and regeneration. Thus the Specific Aims of this proposal are to 1) Determine the influence of NPY signaling on epithelial and mesenchymal cells during LG development; and 2) Determine the effects of NPY signaling on LG regeneration. These aims will be achieved using a combination of mouse genetics in conjunction with genetic, ex vivo organ, biochemical, immunochemical, and fluorescence imaging techniques. My rationale for investigating this hypothesis is that understanding the effects of innervation on lacrimal gland morphogenesis and regeneration and the mechanisms that regulate these processes will enable the design of targeted regenerative approaches to reverse lacrimal dysfunction.